Every patient family we treat at St. Louis
Childrenâ&#x20AC;&#x2122;s Hospital has a unique and special
story. Many end in triumph, others in tragedy.
We have scientific discovery, passion and
courage to thank for the triumphs. The tragic
outcomes drive our pediatric researchers to
change future narratives and put more stories
in the triumphant column.

Photo: Fluorescence microscopic view of cancer cells

A MESSAGE FROM CDI LEADERSHIP

We are proud to present the 2017
Children’s Discovery Institute (CDI)
Investor Report. This year we are sharing
stories of courage, hope and inspiration
generated by the patients we treat and
the physician scientists who work at
both the bedside and the bench, turning
clinical challenges into research inquiries.
The CDI has come a long way in a relatively short
amount of time. Since 2006, this unprecedented
partnership between St. Louis Children’s Hospital
and Washington University School of Medicine has
inspired researchers of all disciplines to think about
what they can do to transform child health worldwide.
The promise of a CDI grant sparks innovation that
makes us think about childhood disease in new ways.
Over the past 11 years, CDI studies have advanced
the field of genomics-based, personalized treatments
for children with common diseases, such as asthma
and childhood infections, as well as those with rare
and neglected diseases, birth defects, or metabolic
and immunological disorders.
Your support of pediatric research is like a tsunami.
The research it enables gains strength quietly out of
sight, surfacing first as a published study that causes
ripples through the scientific community. When those
ripples come together they gain momentum and
soon become a force that changes the landscape
of pediatric disease as we have known it.

The research studies we present in this report all hold
the promise of great change in the way we diagnose,
treat and think about childhood disease. These are great
adventures that propel us to keep asking, keep reaching
and keep fighting as long as there are childhoods being
threatened by illness. Thank you for joining us. The best
is yet to come.

PROTECTING OUR MOST VULNERABLE
Nearly 120,000 babies are affected by birth defects each year.
For some, the causes are unknown. Those are the focus of
a CDI-funded research team determined to help families by
providing them with a diagnosis. Meanwhile, other CDI-funded
researchers are working to protect vulnerable premature infants
from a dangerous infection that plagues babies in neonatal
intensive care units worldwide.

Birth defects are a major cause of infant
death in the United States. Despite their
prevalence, researchers know little about
their causes. To address this knowledge gap,
next-generation genomics analyses of
patients with birth defects and their family
members permit discovery of possible gene
variants that can be tested for function in
model systems, such as worms or zebrafish.
Watching how these models develop will
help CDI researchers understand how
birth defects develop in children.

GENOMICS OF BIRTH DEFECTS
In 2014, CDI funding enabled a collaboration between
Washington University School of Medicine experts
in newborn medicine, genetics, genomics, pediatric
cardiology, critical care medicine, computational biology
and developmental biology. Their focus has been to
identify genetic problems in babies and young children
who otherwise would not have a diagnosis.
“Once we confirm a birth defect of currently unknown
origin and enroll the family in our study, we collect the
DNA from the affected baby, siblings and both parents.
Then we look across the entire genome to see if we
can identify the gene code anomaly that has caused
the problem,” says co-principal investigator and the
Park J. White, MD, Professor of Pediatrics, F. Sessions
Cole, MD. The study also involves, on a day-to-day
basis, co-principal investigator Jennifer Wambach, MD,
newborn medicine; Dustin Baldridge, MD, newborn
medicine; and Dan Wegner, laboratory manager.
It sounds fairly straightforward, but Dr. Cole says because
all humans carry millions of gene code differences, trying
to sort through them to find which one created the defect
can seem like an insurmountable challenge. In fact, it
takes the high level of computational firepower at the
McDonnell Genome Institute at Washington University
to make that type of needle-in-a-haystack work possible.

4

The Genomics of Birth Defects project has enrolled
more than 100 infants and children with structural
birth defects, along with their families. So far, the study
has provided diagnoses for around 25 percent of these
families. Most of these infants and children have birth
defects involving a single organ system, such as the
heart, lung or brain, but 30 percent have birth defects
involving multiple organ systems.
“We are one of the first research projects in the country
using whole genome sequencing — a deep dive into
more than three billion DNA base pairs —as opposed
to exome sequencing, which only looks at the genetic
code inside genes,” says Dr. Baldridge, who has been
able to pursue a research career in genetics with the
CDI funding of this project. “That means we’ve been
able to expand our search of gene code problems from
one percent to 100 percent of the base pairs that make
up the human genome.”
Once a candidate gene code problem is identified, the
team turns to a model system, such as mice or zebrafish,
to confirm that it is what has caused the defect. “The
CDI has allowed us to build a bridge between patients
in the genetics clinic, the McDonnell Genome Institute
and basic science investigators throughout the School of
Medicine to help families solve their medical mysteries,”
Dr. Baldridge says.

PROTECTING OUR MOST VULNERABLE The Genetics Of Birth Defects

THE STORY

gabby’s
hope
During a routine sonogram, Mike and Leslie Macari
were told something was wrong. Their baby was
too small. Her skull was shaped abnormally, and
there was evidence of potential heart problems.
An amniocentesis procedure performed to rule
out chromosomal abnormalities revealed nothing.
Other tests were also inconclusive.
So the Macaris waited, and on June 23, 2016, their
daughter Gabrielle was born. At only 3 lbs., 12 oz.,
she was transported to Children’s, where the neonatal
intensive care team would be tasked with helping
little Gabby gain weight and begin to thrive.
As Gabby struggled, an array of specialists visited to
see if they could offer their expertise and help provide
a diagnosis.
“We were told that, with all the different things going
on with Gabby, we were probably looking at some
sort of syndrome,” says Mike. “However, Gabby’s
symptoms didn’t match up with any known disease.
As a parent, not knowing what is wrong with your
child is very difficult.“
The genetics team eventually gave Gabby a clinical
diagnosis of neonatal progeroid syndrome (WiedemannRautenstrauch syndrome), a very rare disease that has
been found in only 40 documented cases throughout
the world. Among other things, this rare genetic
syndrome is characterized by an aged appearance at
birth, severe growth restrictions and a shortened life
span. Most infants don’t live longer than 7 months.

to peel back the onion of a family’s genome to provide
them with long-sought answers. Sequencing revealed
that Gabby had variants in the POLR3A gene. Deeper
digging uncovered other families throughout the
world who had children with the same diagnosis, and
the CDI’s genetic testing of these other children verified
their gene variants were similar to Gabby’s. One of
these families had a 16-year-old with this syndrome.
“The Genomics of Birth Defects study by the CDI has
allowed us to find answers we have sought for a very,
very long time about our daughter,” Mike says. “It has
allowed us to have hope and find other families who
share in our extraordinary journey. It has given them
hope as well.”
“Plus,” Mike adds, “Gabby now has the opportunity to
leave a lasting legacy of making the world a better place
for children. She has already made an important and
inspiring contribution to science. Suddenly, Gabby’s
prognosis went from 7 months to the sky’s the limit.”

“The Genomics of Birth Defects study by
the CDI has allowed us to find answers
we have sought for a very, very long
time about our daughter.”
For now, the Macaris are busy enjoying a happy little
girl, who celebrated her first birthday with a taste of
pink frosting from a cupcake she shared with her
mom, dad and 4-year-old brother.

Looking for hope, Mike and Leslie decided to
participate in a CDI-supported study designed
5

STOPPING
NEC &
REVERSING
SHORT BOWEL
SYNDROME

PROTECTING OUR MOST VULNERABLE

Necrotizing enterocolitis (NEC) is the most
common and lethal gastrointestinal disease
in preterm infants. It happens when bacteria
invades the small intestine, causing infection
and inflammation that ultimately destroys
the wall of the bowel. Because its origins
are unknown, no preventive strategy has
meaningfully reduced its frequency. Once
the disease takes hold, surgery to remove
the dead tissue is the only treatment option
currently available. This measure leaves the
infant with insufficient intestine to absorb
nutrients for growth, known as short bowel
syndrome, and sentences them to the lifelimiting fate of receiving the nutrition they
need through a feeding tube.

Photo: The human intestine at 17 weeks (Source: Misty Good, MD)

7

THE SCIENCE

Brigida Rusconi, PhD

METABOLOMIC AND EXPERIMENTAL INVESTIGATION OF
HOST LIPIDS IN NECROTIZING ENTEROCOLITIS ONSET
Brigida Rusconi, PhD, pediatrics, applied for and received a CDI fellowship to join in
the work of Phillip Tarr, MD, the Melvin E. Carnahan Professor in Pediatrics at the School
of Medicine. His lab works to identify and quantify differences between microbial
communities in the guts of infants who develop NEC and those who don’t. Now, with
CDI funding of her own, Dr. Rusconi will employ the bank of fecal samples collected
with support from prior CDI funding granted to Dr. Tarr and Barbara Warner, MD,
pediatrics, to look for markers that could be used to alert clinicians that an infant
is at risk for developing NEC. Dr. Rusconi is most interested in describing the role
a certain type of lipid plays in that development.

Now, with CDI funding of her own, Dr. Rusconi will employ the
bank of fecal samples collected with support from prior CDI
funding granted to Dr. Tarr and Barbara Warner, MD, pediatrics,
to look for markers that could be used to alert clinicians that
an infant is at risk for developing NEC.
“I have always been interested in this interface between host and pathogens,”
Dr. Rusconi says. “How do such small bugs have such a big effect on us? To pursue
that question, I’ve moved from classical microbiology to integrated translational
research, looking at samples from the human population to investigate how
they are influenced by bacteria. That’s why I came to Washington University.”

MODULATING THE INTESTINAL IMMUNE
RESPONSE IN THE PATHOGENESIS OF
NECROTIZING ENTEROCOLITIS

HIGH CONTENT DRUG SCREENS FOR
THE PREVENTION OF NECROTIZING
ENTEROCOLITIS

At the University of Pittsburgh School of Medicine,
Misty Good, MD, pediatrics, and her team used a
mouse model to show that a compound in amniotic
fluid inhibits gut inflammation. Now a neonatologist at
St. Louis Children’s, Dr. Good will use her CDI funding
to explore the compounds in breast milk that offer the
same protection and find out how to activate those
compounds through nutritional supplementation.
She also is interested in understanding the signaling
pathways that are involved in NEC development and
predicting the infants at risk for NEC.

With their CDI funding, Clifford Luke, PhD, pediatrics;
and Stephen Pak, PhD, pediatrics, are capitalizing on
the translucence of a worm (C. elegans) to model
intestinal cells under attack to develop and perform
drug screens for compounds that could prevent NEC.

“Because we are saving younger and younger babies,
we are seeing more vulnerability to NEC,” Dr. Good
says. “Our goal is to protect them so they have a
chance to lead healthy lives.”

Now a neonatologist at Children’s,
Dr. Good will use her CDI funding to
explore the compounds in breast milk
that offer the same protection and find
out how to activate those compounds
through nutritional supplementation.

The investigators recently created a
method to measure cell death and have
conducted a pilot screen using a library
of FDA-approved drugs.
The investigators recently created a method to measure
cell death and have conducted a pilot screen using
a library of FDA-approved drugs. After validation
of potential protective compounds in worms, the
researchers will test candidate drugs for efficacy in
NEC mouse models. Ultimately, the investigators
hope to find a drug that can protect babies from
this life-threatening disease.

9

THE SCIENCE

Kristen Seiler, MD

DEVELOPMENT OF PATIENT-DERIVED SMALL INTESTINE
“ORGAN-ON-CHIP” MICROFLUIDIC DEVICES
Like Dr. Rusconi, Kristen Seiler, MD, surgery, chose to pursue a surgical residency
at the School of Medicine based on the strength of its resources and expertise in
NEC. She works in the lab of Brad Warner, MD, the Jessie L. Ternberg, MD, PhD,
Distinguished Professor of Pediatric Surgery and the Children’s Hospital surgeon-inchief, to explore small intestine regeneration. Her research seeks to understand the
multilevel cellular interactions necessary to grow the human epithelium that lines
the intestine. That knowledge could advance approaches for organ regeneration.

Her research seeks to understand the multilevel cellular
interactions necessary to grow the human epithelium that lines
the intestine. That knowledge could advance approaches for
organ regeneration.
“My organ of interest has always been the small intestine, so when I was in medical
school I did research on small intestine regeneration and was very interested in
Dr. Warner’s work,” Dr. Seiler says. With her CDI funding, Dr. Seiler will line a
microchip with living small intestine cells and watch how they develop the protective
wrap that keeps toxins out and lets nutrients into the small intestine and the blood
vessels that provide the oxygen the organ needs to live. “If we can understand
what triggers gut growth, then maybe we could someday restore a child’s
intestinal health and the ability to absorb nutrients.”

veyda’s
VICTORY
She’s a 6-year-old fighter who makes going up against
Fortunately, Veyda qualified for a bowel lengthening
short bowel syndrome look like child’s play. Veyda
procedure that pediatric surgeon Brad Warner, MD,
was born with gastroschisis, a birth defect of the
has in his collection of solutions to restore the
abdominal wall that caused a small hole beside her
intestines of children with short bowel syndrome.
belly button through which her intestines protruded.
In the process, they became twisted, cutting off blood
flow and causing them to die. This required immediate
surgery to remove the dead tissue. Left with only about
half the length of a normal intestine, she is unable to
absorb necessary nutrients and fluids. She must be
fed through an intravenous tube, making her prone to
life-threatening infection. “We’ve been on antibiotics
for years trying to get rid of the bad bacteria in her gut,”
says Veyda’s mom, Elise. After years of being under
siege, Veyda’s intestines had become dilated, causing
“Dr. Warner is amazing. We feel so lucky to have him
chronic diarrhea and a painfully distended tummy.
in our corner,” Elise says. “In fact, we’re grateful for
everything Children’s Hospital has done for us. It’s our
“Earlier this year, we realized that we had to do
second home.” That said, Elise and her husband, Adam,
something,” Elise says. “She just didn’t want to live like
are rooting for the researchers working to make short
that anymore. She wants to be a normal kid who goes
bowel syndrome a thing of the past.
to school, plays with her friends, enjoys a sleepover.”

“Dr. Warner is amazing. We feel so lucky
to have him in our corner,” Elise says.
“In fact, we’re grateful for everything
Children’s Hospital has done for us.
It’s our second home.”

11

PEDIATRIC
CANCER
RESEARCH

AS LONG AS THEY FIGHT, WE FIGHT
On multiple fronts, CDI investigators fight for children who
are battling disease and facing seemingly insurmountable odds.
At the same time, pediatric researchers compete for scarce
public funding resources to fund studies in pediatric cancers,
chronic respiratory diseases, congenital heart disease and
disorders of the immune system. Despite the challenges, they
are making gains by using seed money from the CDI to fund
their urgent search for more targeted, more precise and more
personalized treatments.

Cancer is the leading cause of disease-related
death in children under 15 in the United States.
The incidence of pediatric cancer has risen
about one percent annually for the past 35 years,
yet, only four percent of National Cancer Institute
funding is dedicated to pediatric cancer research.
That is partly why fewer than 10 drugs have been
developed to treat pediatric cancer since 1990.
Researchers need philanthropic support
to close that funding gap and save the lives
of generations to come. And — because adult
survivors of pediatric cancer are twice as likely
as the general population to develop cancer —
save those lives, too.

Washington University School of Medicine bioengineers
Yongjian Liu, PhD, and Hong Chen, PhD, are using CDI
funding to develop an innovative strategy to treat the
single greatest cause of brain tumor–related deaths in
children — diffuse intrinsic pontine glioma (DIPG).

Jeffrey Bednarski, MD, PhD, pediatrics; Todd Fehniger,
MD, PhD, medicine; and Rizwan Romee, MD, medicine,
have joined forces to create hope for children with
acute myeloid leukemia (AML). This type of cancer
has remained a challenge to treat, requiring many
to undergo a bone marrow transplant. For patients
who relapse after transplant, no viable options for
treatment exist.

Traditionally, the location and scattered nature of DIPG
prohibits surgery. Moreover, the disease does not
respond to radiation and chemotherapy. Working to
provide clinicians with more options, this research team
will test the effectiveness and safety of using focused
ultrasound to noninvasively, locally and temporally open
the blood-brain barrier, which prevents most drugs
from reaching the brain tissue. That would allow for
ultra-small nanoclusters loaded with an imaging agent
and chemotherapy drugs to reach the tumor.
Drs. Chen and Liu are testing this novel approach in
collaboration with Children’s pediatric neuro-oncologist
Joshua Rubin, MD, PhD, using brain tumor models
based in mice.

Working to provide clinicians with more
options, this research team will test the
effectiveness and safety of using focused
ultrasound to noninvasively, locally and
temporally open the blood-brain barrier.

Their small, phase 1, “first-in-human”
clinical trial provided evidence that the
immune system’s “natural killer” (NK) cells
can be dialed up in the laboratory, trained
to recall that activation and then unleashed
to destroy cancer cells in some patients.
This research team wants to develop an option by trying
to mirror the success Drs. Fehniger and Romee had in
showing promise for immunotherapy in treating adults
with AML. Their small, phase 1, “first-in-human” clinical
trial provided evidence that the immune system’s
“natural killer” (NK) cells can be dialed up in the laboratory,
trained to recall that activation and then unleashed to
destroy cancer cells in some patients. Responses to the
treatment were observed in five of the nine adult patients
that could be evaluated.

To ensure they are hitting their targets, the researchers
track the nanoclusters using PET imaging and modeling
technologies developed by Dr. Liu’s colleague,
Yuan-Chuan Tai, PhD, at Washington University’s
Mallinckrodt Institute of Radiology.

14 AS LONG AS THEY FIGHT, WE FIGHT Pediatric Cancer Research

THE STORY

victoria’s
ride
December 2017 will mark the 11th year Victoria Drier
has been battling brain cancer. She was 16 when terrible
headaches led her to Children’s Hospital after an MRI
at a separate facility revealed a tumor the size of two
golf balls. Victoria went through a full craniotomy with
pediatric neurosurgeon Matthew Smyth, MD, to remove
the tumor and then had radiation therapy at Siteman
Cancer Center.

and pediatric cancer research. Victoria was the
inspiration for the cause’s Ride for a Child program,
having served as Children’s Hospital’s first patient
ambassador. David now serves as president of the Pedal
the Cause board of directors. Its goal is to make sure
100 percent of all donations stay in St. Louis to fund the
work of cancer researchers at Siteman Cancer Center
and the McDonnell Pediatric Cancer Center of the CDI.

Victoria went on to graduate from high school.
Then, during her freshman year of college, another
tumor emerged in the same place. Once again,
Dr. Smyth removed it. He has since performed four
more surgeries on Victoria. The most recent one was
in May 2017, a less-invasive image-guided ablation.
She also has been to two other children’s hospitals
to take part in clinical trials of experimental radiation
and chemotherapy. Along the way, Victoria and her
family have been contributing to scientific discovery
here at home.

Thanks to funding from the CDI,
each of her tumors has been stored
in a tumor bank first overseen by
pediatric oncologist Joshua Rubin,
MD, PhD, pediatrics.

Thanks to funding from the CDI, each of her tumors has
been stored in a tumor bank first overseen by pediatric
oncologist Joshua Rubin, MD, PhD, pediatrics. Victoria
is now undergoing an innovative personalized treatment
involving a vaccine made from her most recent
tumor’s DNA.
Leaving nothing to chance, Victoria’s parents, Julie
and David Drier, became involved in Pedal the Cause,
an annual cycling event that raises money for adult

After so many years and so many interruptions of her
adolescence, her education and her young adulthood,
one might expect Victoria to be bitter. To that she says,
“What good would that do? This was no one’s fault.”
Instead, Victoria remains upbeat and grateful for the
care she has received. “All my doctors have been
the best, and my family could not be more supportive.
We are a great team.” With all the advancements in
cancer research, Victoria says, “I am more hopeful
than ever that I will continue to live a high quality of
life while effectively managing my cancer, and maybe
even contribute to finding a cure.”
15

THE SCIENCE
donor as a reagent or “living drug” without risk of lifethreatening donor toxicity, called graft vs. host disease
(GvHD). The research team will use its CDI funding to
further optimize multiplex gene edited CAR-T to treat
T-cell malignancies in children and adults. Additionally,
they will develop strategies to overcome life-threatening
cytokine release syndrome (CRS), a major limitation of
adoptive T-cell immunotherapies in general. Finally, the
DiPersio team incorporated a novel “suicide gene” in the
CAR-T that will allow for their elimination, if needed, as
well as to track these genetically manipulated T-cells in
humans using a unique form of PET scanning.
Shalini Shenoy, MD; Robert Fulton;
John F. DiPersio, MD, PhD

CLINICAL DEVELOPMENT OF CRISPR/CAS9
GENE EDITED CAR-T FOR THE TREATMENT
OF T-CELL MALIGNANCIES
Children who develop T-cell acute lymphoblastic
leukemia (T-ALL) face a difficult road. Even after
aggressive combination chemotherapy, the disease
frequently returns, requiring allogeneic stem cell
transplantation. In spite of these aggressive measures,
the outcome for children with relapsed T-ALL is
very poor.
But there is new hope based on recent advances
made in the treatment of another form of leukemia,
B-cell leukemia (B-ALL) and lymphoma (B-NHL).
Research breakthroughs have shown a novel form of
immunotherapy using chimeric antigen receptor T-cells
(CAR-T) to be extremely effective in the treatment of
relapsed B-ALL and B-NHL. However, using CAR-T cells
for the treatment of T-cell malignancies presents several
significant challenges that so far have prevented the
use of CAR-T or other targeted immune therapies to
treat these devastating diseases. A group of Washington
University School of Medicine researchers will work
to overcome those obstacles.
The team is led by internationally known investigators
John F. DiPersio, MD, PhD, medicine; and his colleague
Matthew Cooper, PhD, medicine, along with pediatric
hematologist/oncologist Shalini Shenoy, MD and
Robert Fulton, a scientist at the Washington University
McDonnell Genome Institute. They will use gene
editing to develop an “off-the-shelf” CAR-T product that
prevents CAR-T cells from attacking either each other
or non-cancer cells in the patient. In addition, by also
editing part of the T-cell receptor itself, these “multiplex
gene edited” CAR-T cells can be used from any

Their studies will potentially yield the “first-in-human”
CAR-T therapy for children and adults with relapsed
T-ALL and T-NHL. The next step will be to test this
approach in clinical trials. In addition, successful
identification of new genetic and/or pharmacologic
approaches to mitigate cytokine release syndrome will
expand the clinical use and safety of CAR-T and advance
the fields of CAR-T for both T- and B-cell malignancies
in the future.

Gavin Dunn, MD, PhD; Karen Gauvain, MD

A PILOT STUDY OF A PERSONALIZED VACCINE
APPROACH IN PATIENTS WITH RECURRENT
PEDIATRIC BRAIN TUMORS
In another newly funded clinical trial in pediatric
cancer research, Karen Gauvain, MD, pediatrics; and
Gavin Dunn, MD, PhD, neurosurgery, hope their study
will lead to more effective treatments for children with
recurrent brain tumors. Currently, very few options are
available. This project is the first-ever clinical trial to treat
pediatric patients experiencing relapsed or recurrent
brain tumors with a personalized vaccine — referred to
as a peptide vaccine — developed by targeting genetic
abnormalities unique to each individual tumor. The
researchers will benefit from the School of Medicine’s
emergence as a world leader in developing personalized
vaccines to fight cancer.

16 AS LONG AS THEY FIGHT, WE FIGHT Pediatric Cancer Research

THE STORY

simeon’s
comeback
As 10-year-olds go, Simeon Schlaggar was on a
trajectory to success in every aspect of his life. Whether
it was hockey, baseball or his studies at school, Simeon,
whose dad is Bradley Schlaggar, MD, PhD, neurologistin-chief at Children’s Hospital, excelled. But a diagnosis
of T-cell leukemia interrupted Simeon’s progress
and promise.

For eight months in 2016, Simeon went through
body blow after body blow of chemotherapy, in what
Dr. Schlaggar calls a scorched-earth strategy designed
to destroy tumor cells but that also injured his kidneys,
liver and intestines. “My wife, Christina, who had gone
through her own battle with breast cancer, said his
treatment made hers seem like a walk in the park.”

Now, with the CDI - funded research
to bring along the same type of
immunotherapy used successfully in
B- cell leukemia, Dr. Schlaggar sees a
day when future T- cell treatments will
be less toxic and more personalized.

Now in the three-year maintenance stage of treatment,
Simeon is quickly returning to himself, even while
enduring daily meds, monthly infusions, periodic
lumbar punctures and bursts of steroids. “He has
had chemotherapy and pitched later that day,”
Dr. Schlaggar says. “That’s just how resilient he is.”

His doctors fought back with a treatment protocol
that Dr. Schlaggar says is more complicated than the
U.S. tax code. Every stage —induction, intensification,
consolidation, delayed intensification and maintenance—
presents its own set of challenges. “We watched Simi go
from being a strong, healthy kid to someone who didn’t
have the strength to stand up from a seated position or
walk up a flight of stairs,” Dr. Schlaggar says.

Now, with the CDI-funded research to bring along the
same type of immunotherapy used successfully in B-cell
leukemia, Dr. Schlaggar sees a day when future T-cell
treatments will be less toxic and more personalized.
“Our family has learned a lot from this whole process
about what’s really important for life,” Dr. Schlaggar
says. “And, in my own work delivering prognoses to my
patients, I’ve learned that, while 85 percent survival may
sound like a good prognosis to the person delivering
it, it’s not nearly as reassuring as it might sound to
the families who have to face so much uncertainty.”

17

MAKING
PEDIATRIC
TRANSPLANTS
LAST

AS LONG AS THEY FIGHT, WE FIGHT

Most pediatric lung transplant recipients
develop chronic rejection within five years
of transplant. Transplant patients undergo
an immunosuppressive drug regimen, which
helps prevent acute rejection but can lead
to infections that may impact longer-term
transplant outcomes. Rejection medication
can impact the entire body, giving rise to high
blood pressure, high cholesterol, arthritis and
diabetes. In other words, the bodies of children
with transplanted organs age quickly and never
have a chance to bounce back. The next frontier
of pediatric transplant research is already taking
shape, thanks to funding from the CDI and the
drive of its investigators to make life better
for these children.

Photo: Fluorescence microscopic view of human lung fibroblasts

19

THE SCIENCE

Joshua Blatter, MD, MPH

IDENTIFYING BIOMARKERS IN PEDIATRIC LUNG TRANSPLANTATION
USING A COMPLETE MICROBIOME
No lung transplant study has simultaneously examined the bacteria, fungi
and viruses in transplanted lungs in order to identify associations between
the microbiome and transplant outcomes.

The research team is investigating the utility of a particular class
of viruses, called anelloviruses, in helping predict which patients
are more or less likely to have bad outcomes following transplant.
To the researchers, it appears that having more anellovirus after
transplant is actually a good thing.
That is until 2016, when Joshua Blatter, MD, MPH, pediatrics; and David Wang, PhD,
molecular microbiology, embarked on a CDI-funded study to leverage knowledge
from the largest group of pediatric lung transplant recipients in the world to identify
early microbial biomarkers of disease associated with shorter transplanted lung
survival. This is a multi-center effort led by these Washington University School
of Medicine researchers.
The research team is investigating the utility of a particular class of viruses, called
anelloviruses, in helping predict which patients are more or less likely to have bad
outcomes following transplant. To the researchers, it appears that having more
anellovirus after transplant is actually a good thing. Their best guess now is that
when patients are more immunosuppressed, they develop higher levels of this virus.
And patients who are more immunosuppressed are, of course, less likely to reject their
new lungs. So, because of this research, it may be possible for doctors to use this
virus to gauge whether patients are receiving the right doses of immunosuppressants.

20 AS LONG AS THEY FIGHT, WE FIGHT Making Pediatric Transplants Last

THE STORY

kylie’s
FIGHT
Kylie is 13, and so far her life has been about beating
back the symptoms that make cystic fibrosis such a
challenging disease. It progressively debilitates two
organ systems — the lungs and the pancreas — and
often leads to the need for a lung transplant.
Kylie, who is from St. Joseph, Missouri, receives most
of her care from doctors at Children’s Mercy in Kansas
City. But when it came time for her to be put on a
transplant list, those doctors sent Kylie to St. Louis.

Plus, Kylie no longer needs a wheelchair
or an oxygen tank. Instead of fighting
so hard to breathe, she can race her
9-year-old brother and have tickle fights.

“We tried to maintain her lung function to put off a
transplant until she was at least 16,” says Kylie’s mom,
Ramona. “But it just wasn’t working. She was on
oxygen 24 hours a day and could barely walk across
the living room. It was time.”
Kylie received her new lungs on May 21, 2017, and
will have to work the rest of her life to keep them
healthy and away from chronic rejection. “But,”
Ramona says, “that’s easier than cystic fibrosis
treatments.” Plus, Kylie no longer needs a wheelchair
or an oxygen tank. Instead of fighting so hard to
breathe, she can race her 9-year-old brother and
have tickle fights. Homebound for so long, she can
now go to school this fall.
After her transplant, one of Kylie’s first requests was
to have her hair dyed magenta. So, now she’s just a
girl with fun, pink hair, breathing in life.
21

SOLVING
FOR PRIMARY
IMMUNODEFICIENCY

PERSONALIZED MEDICINE
At the genetic level, any two people are more than 99.9 percent
alike. With philanthropic support, Washington University School
of Medicine and St. Louis Children’s Hospital have invested in the
infrastructure necessary to understand the role of genetics in
pediatric disease development.

The body’s immune system is there to protect.
Yet, mutations in the genes of immune cells
can cause a great deal of harm. The CDI funds
impassioned researchers on the forefront of
understanding the biology of the immune
system and the molecular and biochemical
underpinnings of the system’s complex
interactions and functions.

Photo: Neural tissue

23

THE SCIENCE

Megan Cooper, MD, PhD

INVESTIGATION OF SOMATIC DEFECTS IN PATIENTS
WITH AUTOIMMUNE DISEASES
Megan Cooper, MD, PhD, pediatrics and pathology and immunology, leads a
laboratory of scientists interested in the origins of pediatric autoimmune disease.
Specifically, they are interested in whether genetic defects lead to altered immune
cell tolerance and the development of autoimmunity in childhood.
Pediatric autoimmune diseases are often difficult to diagnose and can have devastating
long-term effects on health, including chronic arthritis, organ damage and cardiovascular
disease. Since her original funding from the CDI, beginning in 2010, Dr. Cooperâ&#x20AC;&#x2122;s lab
has identified abnormal immune cells in patients with pediatric-onset autoimmune
disease. She evaluates the function of these immune cells and uses next-generation
DNA sequencing to investigate whether genetic defects are the cause of the
abnormalities. This research could lead to promising new approaches for the diagnosis,
monitoring and treatment of pediatric autoimmune diseases within the next 10 years.

Pediatric autoimmune diseases are often difficult to diagnose
and can have devastating long-term effects on health, including
chronic arthritis, organ damage and cardiovascular disease.

24 PERSONALIZED MEDICINE Solving for Primary Immunodeficiency

THE STORY

chase’s
CHANCE
Chase woke up one morning when he was 9 years old
unable to stretch out his left arm. “My sister thought I
was joking, but when she tried to straighten it, I freaked
out,” says the 19-year-old.
Little by little, all of Chase’s limbs and joints began
betraying him. Although physical therapy at Children’s
Hospital helped, Chase felt his life shrinking, and he
couldn’t do anything about it. He started having what
felt like electric shocks streak through the nerves of
his body. “At some point, I started walking on my knees.
It was the only thing I could do to avoid a wheelchair.”

“That’s okay, though, because I’m sure
Dr. Cooper is going to find a treatment
that will make me healthy again.”
It wasn’t until Chase started having frequent infections
that his doctors began to wonder if the source of
Chase’s condition was his immune system. And that’s
when Chase met Dr. Megan Cooper. “She told me
about a study she wanted to do with me that sounded
pretty cool.”

With Chase’s permission, Dr. Cooper performed
whole exome sequencing of his genes. Studying
the raw data, Dr. Cooper found a mutation in SGPL1,
a gene that encodes a protein called sphingosine
1 phosphate lyase (S1P lyase). The gene was
discovered by Dr. Julie Saba, using experiments
on yeast cells in her Children’s Hospital Oakland
Research Institute lab in 1997. Since that time,
Dr. Saba’s lab has focused on how S1P lyase works,
and how problems with it might cause disease.
She and Dr. Cooper formed a collaboration to
continue studying the disease. Dr. Cooper’s lab
is interested in learning how a deficiency in
S1P lyase changes the immune system. Dr. Saba’s
team is working with cells from patients and
mouse models to uncover potential treatments.
Meanwhile, Chase is undergoing kidney dialysis until
a kidney transplant undoes the damage the disease
has caused. And he’s working hard to learn to walk
again for the fourth time.
“That’s okay, though, because I’m sure Dr. Cooper
is going to find a treatment that will make me
healthy again.”

25

PEDIATRIC
CARDIOMYOPATHY

PERSONALIZED MEDICINE

New CDI research proves that therapies
used to treat adults with heart failure
do not work for children. This finding
opens the door to opportunities to seek
new strategies to help children avoid the
need for heart transplantation and years
of immunosuppression that come with it.

OPPOSING ROLES FOR EMBRYONIC AND BONE MARROW-DERIVED
MACROPHAGES IN PEDIATRIC DILATED CARDIOMYOPATHY
New research by CDI-funded researcher Kory Lavine, MD, PhD, and his collaborators,
just published in the Journal of Clinical Investigation, identified the underlying reason
why children with heart failure do not respond to therapies typically used in adult
patients. Heart failure medications currently used in adults target a process called
adverse remodeling, a common mechanism by which the adult heart responds to
injury. Typical drugs such as beta blockers and ACE inhibitors function to halt or slow
down the remodeling process, reducing scar deposition and maladaptive remodeling
of cardiac tissue. Dr. Lavine’s lab proved that adverse remodeling does not happen in
children with heart failure. These findings provide a framework to understand
why current treatments for heart failure do not work for children and signal that
new approaches are needed.

“We hope to get to the day when a patient gets diagnosed with
heart failure and undergoes routine genetic screening. For
children who carry a heart failure mutation, we hope to either
have identified drugs that target their mutation or engineer a
zebrafish line to better understand their disease and identify
drugs with the potential to reverse the course of their illness,”
Dr. Lavine says.
Working with zebrafish through a recently funded CDI grant, Dr. Lavine’s lab is
beginning to develop new strategies for pediatric heart failure. They are inserting
genetic mutations identified in children with heart failure into the translucent zebrafish.
Then they employ advanced imaging techniques to understand why each pediatric
heart failure mutation results in cardiac dysfunction and screen for drugs that may
serve as precision therapies to treat an individual child’s mutation. “We hope to get
to the day when a patient gets diagnosed with heart failure and undergoes routine
genetic screening. For children who carry a heart failure mutation, we hope to either
have identified drugs that target their mutation or engineer a zebrafish line to better
understand their disease and identify drugs with the potential to reverse the course
of their illness,” Dr. Lavine says.
28 PERSONALIZED MEDICINE Pediatric Cardiomyopathy

THE STORY

layla’s
LEGACY
In 2010, just two days before Christmas, Colleen and
Mike learned that their 6-month-old daughter, Layla,
suffered from dilated cardiomyopathy. As a registered
nurse with cardiac care experience, Colleen knew
her family’s life would never be the same from that
day forward.
“When the diagnosis was cardiomyopathy, we felt
like we were given a death sentence,” Colleen says.
“More than half of all children diagnosed don’t live past
age 5. If they do survive, it is a fluke or due to a heart
transplant, and that is not a cure, since the life span
of a new heart is only around 10 to 15 years.”
Layla spent her first Christmas in the cardiac intensive
care unit at St. Louis Children’s Hospital, and she
had many more hospitalizations, tests and medical
and surgical procedures after that. The Millers’ lives
became filled with doctors’ appointments, medication
schedules and worry, knowing the whole time that a
transplant loomed in their future. That time came in
August of 2014.

The chair has a plaque with Layla’s
name and a quote that has sustained
the Millers through it all. It reads:
“There is no foot too small that it
can’t leave an imprint on this world.”

“We have always had an idea of where the dilated
cardiomyopathy road would lead,” Colleen wrote in
her Caring Bridge blog after learning they were out
of options. “We prayed and worked and gave meds,
faithfully went to doctor’s appointments and spent
many nights in the hospital and cardiac ICU. All of
this was done to keep the worst at bay … knowing
full well it was out of our control.”
Unfortunately, Layla passed away after going into
cardiac arrest during a cardiac catheterization that
was meant to determine the readiness of her lungs to
handle a new heart. Since that devastating day, the
Millers have channeled their grief into acts of kindness,
such as installing a buddy bench at Layla’s school and
purchasing a rocking chair for the cardiac ICU, where
they spent so much time. The chair has a plaque with
Layla’s name and a quote that has sustained the Millers
through it all. It reads: “There is no foot too small that
it can’t leave an imprint on this world.”
To help make that imprint, the Millers also never
shy away from opportunities to raise awareness of
pediatric cardiomyopathy.
“We are thrilled to do anything we can do to keep
Layla’s story going,” Colleen says. “Raising awareness
for a condition that has no cure, limited treatment,
high mortality and needs more funding to find a cure
is a goal of ours.”
29

CURRENT RESEARCH GRANTS

Since 2006, the Childrenâ&#x20AC;&#x2122;s Discovery Institute
has been the engine that drives the focus
on pediatric research, promotes collaboration
between clinicians and investigators, and
leverages new intellectual resources into
the effort through funding specific programs
and projects.

When Bella was 4 years old, a lump found near her right
ear led to a diagnosis of rhabdomyosarcoma (RMS). She was
still fighting three years later when her pediatric oncologist,
Dr. Fred Huang , orchestrated a cast of pediatric and adult
surgical specialists in a 12-hour surgery on her head and
neck, a complex region of the body. Now, at age 10, Bellaâ&#x20AC;&#x2122;s
scans are as clean as those of any healthy 10-year-old girl
poised to take on the world.

Under the guidance of Dr. Leonard Bacharier, St. Louis
Children’s Hospital and Washington University School of
Medicine have been international leaders in clinical
asthma research and care for decades. They have been
central to two pediatric asthma care networks supported by
the National Institutes of Health and are lead sites for two
other studies involving prevention and treatment of severe
asthma. That’s good news for Isaiah and Dina Huddleston,
who receive asthma treatments from a donor-funded
Healthy Kids Express mobile health program that visits
their school.

The Children’s Discovery Institute is a multidisciplinary,
innovation-based research partnership between St. Louis
Children’s Hospital and Washington University School of
Medicine. Launched in 2006, the Institute is focused on
accelerating discoveries in pediatric research to ultimately
find cures for the most devastating childhood diseases
and disorders. We depend on the generosity of our CDI
investors. Thank you for the support that makes you a
Guardian of Childhood.
Learn more at childrensdiscovery.org